Reprogramming the system(Prof Ashford) Flashcards
Eat Less Burn More
List the four treatments of preventing/treating obesity
Lifestyle change, CBT, bariatric surgery (reserved for morbid obesity) and therapeutic agents to reduce body weight
Give examples of noradrenergics in weight loss and give a brief description
Diethylpropion, mazindol and phentermine. Appetite suppressants that inhibit the noradrenaline uptake. They have serious CV side effects.
Give examples of serotonergics in weight loss and give a brief description
Fenfluramine, dexfenfluramine and fluoxetine. Is an appetite suppressant that acts on the 5-HT system
What is fen-phen and what are its side effects
A combination of fenfluramine and phentermine that can cause potentially fatal pulmonary hypertension and heart valve problems
Give examples of sibutramine in weight loss and give a brief description
Meridia and reductil. They decrease food intake and may also increase thermogenesis by selectively inhibiting the re-uptake of noradrenaline, 5-HT and dopamine. They have a CV and stroke risk
Give the other name of rimonabant in weight loss and give a brief description
It counteracts obesity by antagonising the CB1 receptor. Also have potential with addiction (smoking, alcohol, cocaine and opiates. and can improve short term memory. Can cause severe depression and anxiety in some patients as a side effect. Also as endocannabinoids are neuroprotective there are worries about neurodegeneration
Give a brief description of orlistat
It inhibits pancreatic lipase by decreasing triglyceride absorption. It also reduces efficiency of fat absorption in the small intestine but has side effects such as cramping, bloating, flatulence, abdo pain and diarrhoea. You also need to take vitamine supplements due to loss of fat-soluable vitamine and it is not particularly effective.
List some new drugs being developed
Lorcaserin, qsymia, contrave and liraglutide
Give a description of lorcaserin
Agonist at the 5-HT2c receptor but can cause heart valve problems
Give a description of qsymia
Its a combination therapy of phentermine and topiramate (an anti-convulsant) which has cardiac and psychiatric side-effects
Give a description of contrave
Is also known as mysimba. Is a combination therapy of bupropion (a dopamine re-uptake inhibitor) and naltrexone (opioid antagoist). This works because bupropion activates POMC neurons and naltrexone suppresses POMC inhibition
Give a description of liraglutide
It is a GLP-1 agonist licenced for T2DM that has to be administered I.V. It also has a potential for thyroid and pancreatic cancer
What meds should and should not be used in patients with obesity, uncontrolled hypertension and/or heart disease
Do not use sympathomometics (phentermine or diethypropion)
The preferred agents are lorcaserin or orlistat
What meds should be used in patients with T2DM and obesity
GLP-1 analogues, SGLT-2 inhibitors, metformin and pramlintide (induce weight loss)
What anti-diabetic meds cause weight gain
Insulin, insulin secretagogues and TZDs
Give a description of SGLT-2 inhibitors
Inhibit renal glucose transport and increase urinary glucose excretion. They have beneficial effects on body weight, BP and lipid
Describe the molecule DDP4
Is a serine protease that cleaves a number of substrates such as GLP-1 and GIP
How do DDP4 inhibitors work
Inhibition of DPP4 elevates GLP-1/GIP and this stimulates insulin secretion
What is the definition of hybrid drugs
Single molecules acting on more than one receptor
What are the three types of bariatric surgery
Adjustable gastric band (AGB), roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy
Describe AGB surgery
Band at the top of the stomach to limit food entry
Describe RYGB surgery
The digestive tract-re-route, by-passing most of the stomach and part of small intestine. This acts to G.I. transit of food.
Describe VSG surgery
Reduces stomach size by chopping some off and this lowers food intake and gastric emptying is increased
Does bariatric surgery work?
Yes it does in multiple ways. Produces a substantial weight loss of 50% in one year that is is sustainable and can induce a high level of complete resolution on T2DM. This improvement in glucose homeostasis and insulin sensitivity can occur within a week
What is celastrol?
A leptin sensitiser that can cause weight gain (in DIO mice) due to lowered food intake and later increased energy expenditure
What is an alternative to targeting calorie restriction?
Targeting energy expenditure (cellular bioenergetics)
What are the three types of energy expenditure in humans
1) Obligatory energy expenditure (basic cell and organ physiological needs)
2) Physical activity (variable-advances in tech/transport)
3) Adaptive thermogenesis
Describe adaptive thermogenesis
Heat production by an organism in response to changes in environmental temperature or diet. This occurs in BAT and skeletal muscle
Describe the two types of cold induced thermogenesis
Shivering (skeletal muscle) or non-shivering (brown fat)
Does feeding increase or decrease energy expenditure
Feeding increases use of energy (have energy to burn)
What type of energy is often lost when ATP is produced and what causes this?
Heat due to proton leakage
How does the body utilize heat produced by proton leakage
There can be a regulated proton leak in the BAT by UCP-1 (an inner mitochondrial transmembrane protein). UCP-1 allows protons to re-enter the mitochondrial matrix from intermembrane space with heat produced instead of ATP
What activates UCP-1
Long chain fatty acids and free radicals
What are ‘brite’ adipocytes
Basically brown adipose cells surrounded by white adipose cells
What can trigger a precursor to become brite adipocytes
Cold temperatures and chronic beta-3 agonism
Which part of the nervous system switches on cold and diet induced thermogenesis
The sympathetic nervous system
What is different about brown/brite adipocytes
They have numerous oxidative and naturally uncoupled mitochondria that act to dissipate chemical energy (glucose and fatty acids) as heat
What can bone morphogenetic proteins (BMPs) do to BAT
Promote BAT differentiation
What does FGF21 do
Induces expression of thermogenic genes in BAT and WAT
What is the stem cell biology approach to BAT
Isolate progenitor cells (with liposuction) and stimulate them with known factors to promote BAT differentiation or transect with genes known to induce browning and then transplant back into donor
What is the uncoupling targeted therapeutic agent called, how does it work and what is its side effect
2,4-Dintrophenol is a non-selective coupler of mitochondrial oxidation (proton ionophore) which collapses mitochondrial proton gradient with no ATP produced and lots of heat. This can cause fatal hyperthermia.
Where are the UCP 1-5 located in the body
UCP1 in adipose tissue
UCP2,4 and 5 in neurons
UCP2 and 3 in muscle
What is SkQ1
A group of antioxidants (reactive oxidative species (ROS) scavenger)) that targets the mitochondria anti-ageing neuroprotective
What is C12TPP
It acts to uncouple mitochondria by acting to recycle endogenous fatty acids
How does exercise effect the brain
Improves neuronal health and resilience by promoting synaptic plasticity and increasing neurogenesis and angiogenesis. It also increases firing of POMC neurons and diminishes firing of AgRP neurons
